Control of eIF4E cellular localization by eIF4E-binding proteins, 4E-BPs

Liwei Rong; Mark Livingstone; Rami Sukarieh; Emmanuel Petroulakis; Anne-Claude Gingras; Katherine Crosby; Bradley Smith; Roberto D. Polakiewicz; Jerry Pelletier; Maria A. Ferraiuolo; Nahum Sonenberg

doi:10.1261/rna.950608

Control of eIF4E cellular localization by eIF4E-binding proteins, 4E-BPs

¹Department of Biochemistry, McGill University, Montréal, Québec H3G 1Y6, Canada
²Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada
³Cell Signaling Technology, Inc., Danvers, Massachusetts 01923, USA

↵4 These authors contributed equally to this work.

Abstract

Eukaryotic initiation factor (eIF) 4E, the mRNA 5′-cap-binding protein, mediates the association of eIF4F with the mRNA 5′-cap structure to stimulate cap-dependent translation initiation in the cytoplasm. The assembly of eIF4E into the eIF4F complex is negatively regulated through a family of repressor proteins, called the eIF4E-binding proteins (4E-BPs). eIF4E is also present in the nucleus, where it is thought to stimulate nuclear-cytoplasmic transport of certain mRNAs. eIF4E is transported to the nucleus via its interaction with 4E-T (4E-transporter), but it is unclear how it is retained in the nucleus. Here we show that a sizable fraction (∼30%) of 4E-BP1 is localized to the nucleus, where it binds eIF4E. In mouse embryo fibroblasts (MEFs) subjected to serum starvation and/or rapamycin treatment, nuclear 4E-BPs sequester eIF4E in the nucleus. A dramatic loss of nuclear 4E-BP1 occurs in c-Ha-Ras–expressing MEFs, which fail to show starvation-induced nuclear accumulation of eIF4E. Therefore, 4E-BP1 is a regulator of eIF4E cellular localization.

Keywords

Footnotes

Reprint requests to: Maria A. Ferraiuolo, Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montréal, Québec H3G 1Y6, Canada; e-mail: maria.ferraiuolo{at}elf.mcgill.ca; fax: (514) 398-1287; or Nahum Sonenberg, Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montréal, Québec H3G 1Y6, Canada; e-mail: nahum.sonenberg{at}mcgill.ca; fax: (514) 398-1287.
Abbreviations: 4E-BPs, eIF4E binding proteins; eIF, eukaryotic [translation] initiation factor; c-Ha-Ras, cellular Harvey rat sarcoma viral oncogene; DKO, [4E-BP1/4E-BP2] double knock-out; HA, hemagglutinin epitope; MEF, mouse embryonic fibroblast; mTOR, mammalian target of rapamycin.
Article published online ahead of print. Article and publication date are at http://www.rnajournal.org/cgi/doi/10.1261/rna.950608.
- Received December 10, 2007.
- Accepted April 15, 2008.